Targets for Therapy in Biliary Tract Cancers

The New Horizon of Personalized Medicine

Pritish Iyer; Ming-Huang Chen; Lipika Goyal; Crystal S. Denlinger

Disclosures

Chin Clin Oncol. 2020;9(1):7 

In This Article

Abstract and Introduction

Abstract

Biliary tract cancers (BTCs) are a set of molecularly distinct and heterogeneous diseases. While cytotoxic chemotherapy remains the current standard of care for treatment-naïve and treatment-refractory unresectable disease, recently identified mutations driving oncologic development offer opportunities for targeted therapy. Currently, alterations in the fibroblast growth factor receptor (FGFR), isocitrate dehydrogenase (IDH), v-Raf murine sarcoma viral oncogene homolog B (BRAF), DNA damage repair, and HER2 pathways have demonstrated promising new therapeutic avenues, among others, and various studies have demonstrated clinical activity with targeted tyrosine kinase inhibitors and/or antibodies. In this review, we will discuss the currently identified targets for therapy in BTCs and review currently available data regarding clinical development of treatment options in these molecularly distinct subsets.

Introduction

Biliary tract cancers (BTCs) have traditionally been classified according to their location. Intrahepatic cholangiocarcinoma (IH-CCA) arises from the peripheral bile ducts within the liver beyond the secondary biliary radicals while extrahepatic cholangiocarcinoma (EH-CCA) arises from bile ducts outside the liver and can be subclassified into either hilar cholangiocarcinoma or distal cholangiocarcinoma. Gallbladder carcinoma (GBC) arise from the gallbladder. While these anatomic distinctions continue to be highly relevant for the diagnosis, prognosis, and management of BTC, an increasing awareness of their molecular heterogeneity has paved the way for new therapeutic approaches in these diseases.

In China, BTC is the 24th most common cancer and the 17th leading cause of cancer death.[1] The incidence of BTC appears to be increasing globally, due in large part to a rising incidence of IH-CCA.[2,3] In fact, BTCs were the most rapidly rising malignancy in Shanghai, China between 1972 and 1994, with an increase of 119% in men and 124% in women and an incidence rate of ~5.5 per 100,000 people.[4,5] The mortality rate of BTC is 1.8/100,000 in China versus 1.0/100,000 in the United States.[6] Epidemiologic variance between Eastern and Western populations is thought to be due in part to a difference in risk factors. For example, obesity and chronic inflammation from primary sclerosing cholangitis (PSC) are more prevalent in Western countries,[7] whereas the prevalence of the liver parasite Opisthorchis viverrini is significantly higher in Thailand, Laos, and Cambodia.[8,9] The liver fluke Clonorchis sinensis has also been associated with the development of cholangiocarcinoma and is endemic to rural China, especially in the northeastern province of Heilongjiang and the southern provinces of Guangdong and Guangxi.[10,11] Other risk factors for CCA include diabetes, chronic viral hepatitis B or C, anatomical abnormalities in the biliary tract such as choledochal cysts, and Lynch syndrome. Risk factors for GBC include polyps, Salmonella Typhi, and chronic cholecystitis.[12,13]

Unresectable or advanced BTC is associated with a 5-year survival rate of 5–10%.[14] The current standard of care for unresectable BTCs is systemic chemotherapy. Gemcitabine was established as palliative therapy in 1996,[15] and remained the standard of care until the phase III ABC-02 trial demonstrated a survival advantage for the combination of cisplatin and gemcitabine over gemcitabine in the front-line setting for advanced disease [median overall survival (OS) 11.7 vs. 8.1 months, respectively, hazard ratio 0.64, P<0.001].[16] The survival advantage of the combination over gemcitabine alone was confirmed in a Japanese population.[17] Recently, the ABC-06 trial demonstrated a modest survival benefit with oxaliplatin/5-fluoruracil (mFOLFOX) and active symptom control (ASC) after progression on cisplatin and gemcitabine (compared to ASC alone), with a median OS of 6.2 vs. 5.3 months, respectively (adjusted hazard ratio 0.69 (P=0.03).[18]

While cytotoxic regimens continue to be evaluated in clinical trials, several genotyping efforts have identified specific potentially targetable molecular aberrations in BTC and the investigational paradigm for unresectable BTC now includes targeted therapy in the front-line and treatment-refractory settings. An understanding of these evolving treatment paradigms requires an understanding of the molecular and genomic underpinnings of the disease. In this review we identify the molecular aberrations identified in BTC and the emerging therapies which target these molecular mutations (Table 1).

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